Use of tryptanthrin compounds for immune potentiation

Abstract

The invention provides immunostimulatory compositions and methods of administration thereof. Also provided are methods of administering a tryptanthrin compound in an effective amount to enhance the immune response of a subject to an antigen. Also provided are methods of administering an effective amount of a tryptanthrin to stimulate the immune response in a subject for the treatment of cancer. Further provided are methods of administering a tryptanthrin compounds as an immunotherapeutic in the treatment of infectious diseases.

1 : A method of enhancing an immune response in a subject to an antigen, the method comprising administering to a subject an immunogenic pharmaceutical composition comprising the antigen and a tryptanthrin compound adjuvant in an amount effect to provide an enhanced immune response to the antigen relative to the response provided without the tryptanthrin compound adjuvant. 
     
     
         2 : The method of  claim 1 , wherein the antigen is derived from a bacterial, parasitic, viral, or fungal pathogen. 
     
     
         3 : The method of  claim 2  wherein the bacterial pathogen is selected from the group consisting of diphtheria,  staphylococcus , cholera, tuberculosis, tetanus,  streptococcus pneumoniae, streptococcus agalacitiae, streptococcus pyogenes , pertussis,  Neisseria meningitis, Neisseria gonorrheae , chlamydia,  Helicobacter pylori , and  Hemophilus influenza  type B. 
     
     
         4 : The method of  claim 2  wherein the viral pathogen is selected from the group consisting of viral meningitis, rhinovirus, influenza, respiratory syncytial virus, parainfluenza virus, rotavirus, tick borne encephalitis virus, coronaviridae, rhabodoviridiae, VZV, EBV, CMV, HIV, HPV, HSV, HAV, HBV, HCV, and SARS. 
     
     
         5 : The method of  claim 2  wherein the parasitic pathogen is selected from the group consisting of  Plasmodium falciparum, Plasmodium ovate, Plasmodium malariae , and  P. vivax.    
     
     
         6 : The method of  claim 2 , wherein the antigen is associated with a disease selected from the group consisting of BCG, cholera, plague, typhoid, hepatitis B infection, influenza, inactivated polio, rabies, measles, mumps, rubella, oral polio, yellow fever, tetanus, diphtheria,  hemophilus influenzae  b, meningococcus infection, tick borne encephalitis, SARS, HCV, HIV, and pneumococcus infection. 
     
     
         7 : The method of  claim 1  wherein the immune response is the cellular production of one or more cytokines. 
     
     
         8 : The method of  claim 1  wherein the tryptanthrin compound is a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A, B, C, D, E, F, G, and H are independently selected from carbon and nitrogen, or A and B and/or C and D can be taken together to be nitrogen or sulfur; R 1 , R 2 , R 3 , R 4 , R 8 , and R 10  are independently selected from the group consisting of hydrogen, halogen, loweralkyl, alkyl, substituted alkyl, cycloalkyl, heterocyclyl, alkylheterocyclyl, substituted heterocyclyl, substituted alkenyl, amino, (substituted alkyl)(alkyl)amino, imino, haloloweralkyl, hydroxy, alkoxy, substituted alkoxy, hydroxyalkylthio, nitro, alkylsulfonyl, N-alkylsulfonamide, arylalkyl, arylalkylaryl, arylaryl, aryloxy, arylamino, acylamino, acyloxyamino, alkylaminoacylamino, alkylaminosulfonylamino, alkylamino, alkenylamino, dialkylamino, alkoxyalkylamino, alkoxyalkylheterocyclyl, mercaptoalkoxyalkyl, cyano, formyl, —COOR 11  wherein R 11  is hydrogen, loweralkyl, aryl, heterocyclyl, monosaccharide or disaccharide, and —CONR 12 R 13  wherein R 12  and R 13  are independently selected from hydrogen, loweralkyl, aryl, heterocyclyl, saccharide, peptide and amino acid residues; or R 2  and R 3  taken together form a six membered aromatic ring; 
         R 7  and R 9  are independently selected from hydrogen, halogen, loweralkyl, haloloweralkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl or heterocyclylalkyl; and 
         R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10  are absent when the ring atom to which they would otherwise be bonded is sulfur or double-bonded nitrogen; or 
         a pharmaceutically acceptable salt, 
         provided that R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10  are not all hydrogen when A, B, C, D, E, F, and H are carbon. 
       
     
     
         9 : The method of  claim 8 ,
 wherein   A, B, C, D, E, F, G, and H are independently selected from carbon and nitrogen;   R 1 , R 2 , R 3 , R 4 , R 8  and R 10  are independently selected from the group consisting of hydrogen, halogen, loweralkyl, alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, substituted alkenyl, (substituted alkyl)(alkyl)amino, haloloweralkyl, hydroxy, alkoxy, substituted alkoxy, hydroxyalkylthio, nitro, N-alkylsulfonamide, cyano, —COOR 11  wherein R 11  is hydrogen, loweralkyl, aryl, heterocyclyl, monosaccharide or disaccharide, and —CONR 12 R 13  wherein R 12  and R 13  are independently selected from hydrogen, loweralkyl, aryl, heterocyclyl, saccharide, peptide and amino acid residues.   
     
     
         10 : The method of  claim 1  wherein the tryptanthrin compound is a compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein 
         D is carbon or nitrogen, and R 4  is absent when D is N; 
         R 1  is hydrogen, halogen, or loweralkyl; 
         R 2  is hydrogen or halogen; 
         R 3  is hydrogen, halogen, heterocyclyl, substituted heterocyclyl, (substituted alkyl)(alkyl)amino, or hydroxyalkylthio; 
         R 4  is hydrogen, halogen, alkoxy, substituted alkoxy, or hydroxy; 
         R 7  is hydrogen or haloloweralkyl; 
         R 8  is hydrogen, halogen, substituted alkoxy, haloloweralkyl, nitro, N-alkylsulfonamide, substituted alkenyl, substituted alkyl, COOR 11  wherein R 11  is loweralkyl, or —CONR 12 R 13  wherein R 12  and R 13  are independently hydrogen or loweralkyl; 
         R 9  is hydrogen; and 
         R 10  is hydrogen, halogen, or loweralkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 : The method of  claim 1 , wherein the tryptanthrin compound is selected from the group consisting of:
 8-nitroindolo[2,1-b]quinazoline-6,12-dione, and   3,8-difluoroindolo[2,1-b]quinazoline-6,12-dione, and   10-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   1,8-difluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-fluoro-1-methylindolo[2,1-b]quinazoline-6,12-dione, and   8,10-difluoroindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-fluoro-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-chloro-8-iodoindolo-[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-2-iodoindolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-3-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-fluoro-4-hydroxyindolo[2,1-b]quinazoline-6,12-dione, and   N-ethyl-4-(methyloxy)-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxamide, and   3-fluoro-8-[(trifluoromethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   3-[(2-hydroxyethyl)thio]-8-[(trifluoromethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-fluoropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-bromopyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-chloropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-iodopyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   ethyl 5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-9-carboxylate, and   N-octyl-5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-9-sulfonamide, and   10-(trifluoromethyl)pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   (5E)-6-(5,11-dioxo-5,11 dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hex-5-enyl acetate, and   6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hexyl dihydrogen phosphate, and   9-[(trifluoromethyl)oxy]pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   a pharmaceutically acceptable salt of any one of the foregoing.   
     
     
         12 : A method of immunotherapy for the treatment of cancer, the method comprising administering to a subject an immunostimulatory effective amount of a tryptanthrin derivative. 
     
     
         13 : The method of  claim 12 , wherein the tryptanthrin derivative is a compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein 
         D is carbon or nitrogen, and R 4  is absent when D is N; 
         R 1  is hydrogen, halogen, or loweralkyl; 
         R 2  is hydrogen or halogen; 
         R 3  is hydrogen, halogen, heterocyclyl, substituted heterocyclyl, (substituted alkyl)(alkyl)amino, or hydroxyalkylthio; 
         R 4  is hydrogen, halogen, alkoxy, substituted alkoxy, or hydroxy; 
         R 7  is hydrogen or haloloweralkyl; 
         R 8  is hydrogen, halogen, substituted alkoxy, haloloweralkyl, nitro, N-alkylsulfonamide, substituted alkenyl, substituted alkyl, COOR 11 , wherein R 11  is loweralkyl, or —CONR 12 R 13  wherein R 12  and R 13  are independently hydrogen or loweralkyl; 
         R 9  is hydrogen; and 
         R 10  is hydrogen, halogen, or loweralkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 : The method of  claim 12 , wherein the tryptanthrin derivative is selected from the group consisting of
 8-nitroindolo[2,1-b]quinazoline-6,12-dione, and   3,8-difluoroindolo[2,1-b]quinazoline-6,12-dione, and   10-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   1,8-difluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-fluoro-1-methylindolo[2,1-b]quinazoline-6,12-dione, and   8,10-difluoroindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-fluoro-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-chloro-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-2-iodoindolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-3-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-fluoro-4-hydroxyindolo[2,1-b]quinazoline-6,12-dione, and   N-ethyl-4-(methyloxy)-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxamide, and   3-fluoro-8-[(trifluoromethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   3-[(2-hydroxyethyl)thio]-8-[(trifluoromethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-fluoropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-bromopyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-chloropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   9-iodopyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   ethyl 5,11-dioxo-511-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-9-carboxylate, and   N-octyl-5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-9-sulfonamide, and   10-(trifluoromethyl)pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   (5E)-6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hex-5-enyl acetate, and   6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hexyl dihydrogen phosphate, and   9-[(trifluoromethyl)oxy]pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   a pharmaceutically acceptable salt of any one of the foregoing.   
     
     
         15 : A kit comprising a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 A, B, C, D, E, F, G, and H are independently selected from carbon and nitrogen, or A and B and/or C and D can be taken together to be nitrogen or sulfur; 
 R 1 , R 2 , R 3 , R 4 , R 8 , and R 10  are independently selected from the group consisting of hydrogen, halogen, loweralkyl, alkyl, substituted alkyl, cycloalkyl, heterocyclyl, alkylheterocyclyl, substituted heterocyclyl, substituted alkenyl, amino, (substituted alkyl)(alkyl)amino, imino, haloloweralkyl, hydroxy, alkoxy, substituted alkoxy, hydroxyalkylthio, nitro, alkylsulfonyl, N-alkylsulfonamide, arylalkyl, arylalkylaryl, arylaryl, aryloxy, arylamino, acylamino, acyloxyamino, alkylaminoacylamino, alkylaminosulfonylamino, alkylamino, alkenylamino, dialkylamino, alkoxyalkylamino, alkoxyalkylheterocyclyl, mercaptoalkoxyalkyl, cyano, formyl, —COOR 11  wherein R 11  is hydrogen, loweralkyl, aryl, heterocyclyl, monosaccharide or disaccharide, and —CONR 12 R 13  wherein R 12  and R 13  are independently selected from hydrogen, loweralkyl, aryl, heterocyclyl, saccharide, peptide and amino acid residues; or R 2  and R 3  taken together form a six membered aromatic ring; 
 R 7  and R 9  are independently selected from hydrogen, halogen, loweralkyl, haloloweralkyl, cycloalkyl, heterocyclyl, substituted heterocyclyl or heterocyclylalkyl; and 
 R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10  are absent when the ring atom to which they would otherwise be bonded is sulfur or double-bonded nitrogen; or 
 a pharmaceutically acceptable salt thereof, 
 provided that R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10  are not all hydrogen when A, B, C, D, E, F, and H are carbon; 
 one or more containers; 
 one or more antigens; and 
 optionally a delivery device for the compound and the antigen. 
 
     
     
         16 : The kit of  claim 15  wherein the delivery device is a syringe. 
     
     
         17 : The kit of  claim 15  wherein the delivery device is a nasal inhaler. 
     
     
         18 : The kit of  claim 15  wherein the delivery device is a transdermal patch. 
     
     
         19 : The kit of  claim 15  wherein the antigen and the compound are present in the same container. 
     
     
         20 : The kit of  claim 15  comprising a first container and a second container wherein the first container contains the compound and the second container contains the antigen. 
     
     
         21 : The kit of  claim 20  wherein the first container contains a second antigen. 
     
     
         22 : The kit of  claim 15  further comprising a non-tryptanthrin adjuvant. 
     
     
         23 : A small molecule immune potentiating compound selected from the group consisting of:
 2,4-dibromo-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-10-methylindolo[2,1-b]quinazoline-6,12-dione, and   1,1-dimethylethyl 4-(2-fluoro-8-iodo-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)piperazine-1-carboxylate, and   2,4-dibromo-1-fluoro-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-chloro-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dibromo-1-fluoroindolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-2-iodoindolo[2,1-b]quinazoline-6,12-dione, and   8-fluoro-4-hydroxyindolo[2,1-b]quinazoline-6,12-dione, and   N-ethyl-4-(methyloxy)-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazoline-8-carboxamide, and   8-[(trifluoromethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   3-fluoro-8-[(trifluoromethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   9-iodopyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   N-octyl-5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indole-9-sulfonamide, and   10-(trifluoromethyl)pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,1-1-dione, and   diethyl(5E)-6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hex-5-enylphosphonate, and   (5E)-6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hex-5-enyl acetate, and   9-(trifluoromethyl)pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hexyl dihydrogen phosphate, and   9-[(trifluoromethyl)oxy]pyrido[2′,3′:4,5]pyrimido[1,2-a]indole-5,11-dione, and   4-hydroxy-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4-dichloro-8-iodoindolo[2,1-b]quinazoline-6,12-dione, and   2,8-diiodoindolo[2,1-b]quinazoline-6,12-dione, and   2,4,8-triiodoindolo[2,1-b]quinazoline-6,12-dione, and   8-fluoro-4-[(phenylmethyl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-3-morpholin-4-ylindolo[2,1-b]quinazoline-6,12-dione, and   8-(trifluoromethyl)indolo[2,1-b]quinazoline-6,12-dione, and   [(8-chloro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)(methyl)amino]acetic acid, and   4-({2-[(8-chloro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)(methyl)amino]ethyl}oxy)-4-oxobutanoic acid, and   2-[(8-chloro-6,12-dioxo-6,12-dihydroindolo[2,1-b]quinazolin-3-yl)(methyl)-amino]ethyl octanoate, and   3-[(2-hydroxyethyl)(methyl)amino]-8-[(trifluorometh-yl)oxy]indolo[2,1-b]quinazoline-6,12-dione, and   8-chloro-3-[(2-hydroxyethyl)th-io]indolo[2,1-b]quinazoline-6,12-dione, and   6-(5,11-dioxo-5,11-dihydropyrido[2′,3′:4,5]pyrimido[1,2-a]indol-9-yl)hexyl acetate, and a pharmaceutically acceptable salt of any one of the foregoing.